1,4-Dioxamacrolides: Preparation and sensory properties

Article abstract of DOI:10.1055/s-2003-37345

The synthesis of 3-methyl-1,4-dioxacylopentadecan-2-one (12c) and 3-methyl-1,4-dioxacylohexadecan-2-one (12d), two new musk odorants, is described starting from methyl 2-bromopropionic acid (6b) and allylic alcohol, respectively. The key step of the synthesis is the ring-closing olefin metathesis (RCM) to the unsaturated 1,4-dioxamacrolides. Insight into the structure-odor relationship (SOR) is provided by the synthesis of ten related unsubstituted or methyl substituted oxamacrolides. Finally, a four step enantioselective synthesis of both (3R)-(+)- and (3S)-(-)-3-methyl-1,4-dioxacyclopentadecan-2-one as well as (3R)-(+)- and (3S)-(-)-3-methyl-1,4-dioxacyclohexadecan-2-one reveals that mainly the (3R)-(+) enantiomers are responsible for the powerful musky odor characteristic. Their synthesis starts from ethyl (2S)-2-hydroxypropanoate (14) or isobutyl (2R)-2-hydroxypropanoate (15) which were treated under acidic conditions with allyl trichloro-acetimidate (16), followed by titanate mediated transesterification, ring-closing olefin metathesis and hydrogenation.

Full text of DOI:10.1055/s-2003-37345

PAPER
365
1
,4-Dioxamacrolides: Preparation and Sensory Properties
1
M
, 4-Dioxamacrolides:
P
a
reparation
r
a
nd Sen
c
sory Prope
r
u
ties s Eh*
Haarmann & Reimer GmbH, 37603 Holzminden, Germany
Fax +49(553)1903628; E-mail: marcus.eh.me@hr-gmbh.de
Received 29 August 2002; revised 16 December 2002
in the same way from the corresponding hydroxy-oxa ac-
ids.
Abstract: The synthesis of 3-methyl-1,4-dioxacylopentadecan-2-
one (12c) and 3-methyl-1,4-dioxacylohexadecan-2-one (12d), two
new musk odorants, is described starting from methyl 2-bromopro- Kraft et al.2i,6 have described two strategies for the synthe-
pionic acid (6b) and allylic alcohol, respectively. The key step of
sis of 4-methyl-1,7-dioxacyclopentadecan-8-one (5), a
the synthesis is the ring-closing olefin metathesis (RCM) to the un-
powerful musk odorant, which possesses the floral aspects
saturated 1,4-dioxamacrolides. Insight into the structure–odor rela-
of some nitro-musks. Both strategies use the polymeriza-
tionship (SOR) is provided by the synthesis of ten related
tion–depolymerization protocol to close the ring in the fi-
unsubstituted or methyl substituted oxamacrolides. Finally, a four
step enantioselective synthesis of both (3R)-(+)- and (3S)-(–)-3-me-
thyl-1,4-dioxacyclopentadecan-2-one as well as (3R)-(+)- and (3S)-
nal step.
(–)-3-methyl-1,4-dioxacyclohexadecan-2-one reveals that mainly
the (3R)-(+) enantiomers are responsible for the powerful musky
odor characteristic. Their synthesis starts from ethyl (2S)-2-
hydroxypropanoate (14) or isobutyl (2R)-2-hydroxypropanoate
(
15) which were treated under acidic conditions with allyl trichloro-
acetimidate (16), followed by titanate mediated transesterification,
ring-closing olefin metathesis and hydrogenation.
Key words: macrocycles, metathesis, lactones, ring closure, musk
odorants, fragrance, structure–odor relationship
Due to low production cost, nitro-musks and polycyclic
musks became the dominating musk fragrances in per-
fumery. However, the use of nitro-musks and polycyclic
musks was subsequently reduced in recent years because
1
of their poor biodegradability. Hence, the synthesis of
new biodegradable macrocyclic musk odorants has be-
come an important topic of current research interest in the
flavor and fragrance industry. One of the most popular
2
®
Figure 1 Cyclopentadecanolide (1); 1,6-dioxacycloheptadecan-7-
ingredient in perfume oils with musk odor is the macrocy- one (2); 1,7-dioxacycloheptadecan-8-one (3); 1,8-dioxacyclohepta-
®
clic lactone 15-pentadecanolide (cyclopentadecanolide ) decan-9-one (4); 4-methyl-1,7-dioxacyclopentadecan-8-one (5).
(
1). However, not only simple lactones can be of impor-
tance, other interesting materials can bear an additional
heteroatom, e.g. an oxygen atom in the ring.
Here we report the first approach to the oxamacrolides 11
and 12 from α-bromo carboxylic acids 6 and 1,ω-alkenols
7
via 1,ω-dienes 10. The key step in our short route is the
1
,6-Dioxacycloheptadecan-7-one (2), 1,7-dioxacyclohep-
tadecan-8-one (3) and 1,8-dioxacycloheptadecan-9-one
4) are strong smelling musk odorants and their odor to-
macrocyclization reaction of 1,ω-dienes 10 by ring-clos-
ing olefin metathesis (RCM), which was catalyzed by the
ruthenium carbene complex 13. Variation of the numbers
of methylene groups in 7 and 9 offers the advantage to
(
7
®
nality is comparable to that of cyclopentadecanolide (1),
but less intense (Figure 1). The synthesis of 1,6-dioxacy-
cloheptadecan-7-one (2) started from methyl 11-bro-
moundecanoate which was reacted with the monosodium
salt of 1,4-butanediol. The resulting methyl 16-hydroxy-
3
synthesize 15- to 17-membered rings.
The synthesis of 1,ω-dienes 10 started with a nucleophilic
substitution of α-bromo carboxylic acids 6 and 1,ω-al-
kenols 7 to generate 2-alkenylcarboxylic acids 8
1
2-oxopalmitate was condensed to the corresponding
4
polyester, which was subsequently depolymerized. The
1
8
(
Scheme 1). This material 8 was transformed without any
5
,7-dioxa- (3) and 1,8-dioxa - (4) isomers were obtained
purification into the 1,ω-diene 10, which was done by
azeotropic esterification in the presence of 0.05 equiv p-
TsOH. The yields over these two transformations vary be-
tween 61% and 69%. The 1,ω-dienes 10 failed to cyclize
when treated with ruthenium carbene 13, due to the for-
mation of 5- or 6-membered intramolecular chelate struc-
Synthesis 2003, No. 3, Print: 28 02 03.
Art Id.1437-210X,E;2003,0,03,0365,0370,ftx,en;T09502SS.pdf.
©
Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

3
66
M. Eh
PAPER
tures, which were formed from the polar ester group with
Table 1 Sensory Properties of Musk 1,4-Dioxamacrolides.
the evolving carbene species. However, 10 reacted
Compound Sensory properties of 11 and 12
Musk intensity
+
smoothly when exposed to catalytic amounts of 13 in the
9
presence of catalytic amounts of Ti(i-PrO) . Cycloal-
4
1
1a
musky, metallic, reminiscent of hot
kenes 11 were obtained in excellent yield (90–95%) as
mixtures of E- and Z-isomers, which were finally hydro-
genated to the saturated 1,4-dioxamacrolides 12.
iron
1
1b
musky, woody, technical, metallic,
+
reminiscent of hot iron
1
1
1
1
1
1c
1d
1e
2a
2b
musky, sweet-floral, erogenous
++
musky, woody, erogenous, animalic ++
musky, sweet-floral, erogenous
musky, floral, erogenous, metallic
++
++
musky, woody, erogenous, techni-
cal
++(+)
1
1
1
2c
2d
2e
musky, sweet-floral, ambergris,
erogenous, reminiscent of musk am-
brette
+++
musky, woody, ambergris, eroge-
nous, animalic, reminiscent of nitro-
musk
+++
musky, sweet-woody, ambergris,
erogenous, reminiscent of musk am-
brette
++(+)
racemization can take place. In contrast, O-alkylation un-
der acidic conditions with trichloroacetimidate was re-
ported to give the ether in good yield and without
racemization.11 In order to preserve the chiral informa-
tion, the etherification of ethyl (2S)-2-hydroxypropanoate
(
14) or isobutyl (2R)-2-hydroxypropanoate (15) was car-
ried out with allyl trichloroacetimidate (16) and in the
presence of catalytic amounts of trifluoromethanesulfonic
acid. Using this procedure we obtained the (2S)- and (2R)-
2
-allyloxyesters 17 and 18 in 75% yield. Allyl trichloro-
Scheme 1 (a) NaH (2.0 equiv), THF, 66 °C; (b) p-TsOH (0.05 acetimidate (16) was readily available from the corre-
equiv), toluene, Dean–Stark,
6
h,
2
steps 61–69%; (c)
sponding allylic alcohol, trichloracetonitrile and a
catalytic amount of sodium hydride. Thereafter, titanate
mediated transesterification by means of 7 mol% Ti(i-
Cl (Cy P) Ru=CHPh (13, 3 mol%), Ti(i-PrO) (0.3 equiv), CH Cl ,
2
3
2
4
2
2
4
0 °C, 90–95%; (d) Pd/C (5 mol%), H , i-PrOH, 72–80%.
2
1
2
PrO) in 1,ω-alkenol 9a or 9b provided dienes (S)- and
4
We noticed different sensory properties for 11 and the sat-
urated counterparts 12, as well as for the unsubstituted and
methyl substituted molecules.
(
R)-10c, as well as (S)- and (R)-10d as suitable cyclization
precursors. Under these conditions the (S)- and (R)- termi-
nal dienes (10) were isolated in 80% yield and an enanti-
The macrocycles 12c,d show an interesting odor profile, omeric excess of ≥95%, which was measured by chiral
and they possess a stereogenic center (Table 1). Therefore GC (for detailed description see Experimental section).
it seemed to be of interest to investigate which enanti- RCM was then effected in the presence of catalytic
omers are responsible for the very pleasant odor of the amounts of ruthenium carbene complex 13 as described
racemates (±)-12c,d.
before, to obtain the (S)- and (R)- unsaturated oxamac-
rolides 11 in excellent yields of 95%. Subsequent hydro-
genation with Pd/C as catalyst in i-PrOH afforded the (S)-
and (R)- oxamacrolides 12 in 75% yield and an enantio-
meric excess ≥95%, which was also measured by chiral
GC.
The synthesis of the enantiomerically pure macrocycles
(
S)- and (R)-12c, as well as (S)- and (R)-12d started from
chiral ethyl (2S)-2-hydroxypropanoate (14) or isobutyl
2R)-2-hydroxypropanoate (15) which are suitable start-
ing materials for the enantioselective approach
(
(
Scheme 2). The O-alkylation of these chiral building All (R)-enantiomers possess an intense and stronger musk
blocks under basic conditions was not practical, because odor than the corresponding (S)-antipodes, and in addition
1
0
Synthesis 2003, No. 3, 365–370 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
1,4-Dioxamacrolides: Preparation and Sensory Properties
367
Table 2 Sensory Properties of 3-Methyl-1,4-dioxamacrolide Enan-
tiomers.
Compound Sensory properties of 11 and 12
Musk intensity
++
(
R)-11c
musky, sweet-floral, ambergris,
erogenous
(
(
S)-11c
R)-11d
slightly musky, sweet-floral
+
musky, woody, ambergris, eroge-
nous, animalic
++
(
(
S)-11d
R)-12c
slightly musky, woody, erogenous
+
strong musky, sweet-floral, eroge-
nous, animalic, ambergris
+++
(
(
S)-12c
R)-12d
musky, sweet-floral, erogenous
++
strong musky, woody, erogenous,
animalic, ambergris
+++
(
S)-12d
musky, woody, erogenous
++
study of structure–odor relationships. Finally, it is worth
mentioning that: (i) all synthesized 1,4-dioxamacrolides
possess musky odor; (ii) a methyl substitution at the C3-
position gives these molecules an unique ambergris note;
and (iii) the (R)-enantiomers are responsible for the typi-
cal odor of the racemates.
Reagents and solvents were purchased from Sigma–Aldrich (De-
isenhofen, Germany) or Acros Organics (Schwerte, Germany) and
used without purification. FC: Biotage Flash 40 equipment with dis-
posable pre-packed columns. NMR: Varian VXR400S or Gemini
2
000 (CDCl , TMS). GC–MS: HP MSD 5972 A (EI: 70 eV) Pola-
3
rimetry: Schmidt and Haensch Polartronic 1 (CHCl ). Chiral GC:
3
Carlo Erba 5300, 25 m × 0.25 mm DMTBS-β-cyclodextrin (Mega),
1
.0 bar H , 100–102 °C/min–180 °C.
2
(
(
)-3-Methyl-1,4-dioxacyclopentadecan-2-one (12c)
)-2-(Allyloxy)propanoic Acid (8b)
In a 100 mL, 3-necked flask fitted with condenser, dropping funnel
and thermometer were placed NaH (60% in mineral oil, 2.40 g, 60.0
Scheme
2
Synthesis of enantiomerically pure 3-methyl-1,4-
mmol) and THF (40 mL). Under N , allyl alcohol (7a) (4.40 g, 75.0
2
dioxamacrolides.
mmol), dissolved in THF (10 mL), was added with stirring at r.t.
Subsequently 2-bromopropanoic acid (6b) (7.60 g, 50.0 mmol), dis-
solved in THF (10 mL), was added and the slurry was heated to re-
flux. After 6 h the mixture was allowed to cool and quenched with
the (R)-enantiomers shows ambergris nuances in combi-
nation with stronger erogenous undertones (Table 2). It HCl (2 M; 40 mL). The aq layer was separated and extracted with
can be concluded that mainly the (R)-enantiomers are re- EtOAc (3 × 100 mL). The organic extracts were combined, dried
(
(
Na SO ), and concentrated on a rotary evaporator to give crude
±)-2-(allyloxy)propanoic acid (90%) (8b: 6.60 g, 92%). The crude
sponsible for the typical odor of the racemates. These re-
sult is in good agreement with the results of other
groups; e.g. Kraft et al. has examined the odor prop-
2 4
product was used in subsequent reactions without purification.
1
3
2i,6
erties of (R)- and (S)-5, and it could be shown, that the (R)-
(
)-9-Decenyl 2-(allyloxy)propanoate (10c)
A mixture of crude (±)-2-(allyloxy)propanoic acid (90%) (8b) (3.30
±)-5; its enantiomer (S)-5 was odorless on GC/olfactom- g, 23.0 mmol), 9-decen-1-ol (9a) (5.50 g, 35.0 mmol) and p-
(
(
–)-enantiomer (R)-5 was the odor vector of the racemate
etry.
TsOH⋅H O (0.38 g, 2.00 mmol) in toluene (40 mL) was refluxed in
a Dean–Stark apparatus for 5 h. After the mixture had cooled to r.t.
the organic layer was neutralized by washing with sat. aq NaHCO3
2
In summary, we have achieved a four-step synthesis to
saturated oxamacrolides with a 1,4-dioxa substructure in
(30 mL), the layers were separated, the organic layer was dried
racemic and enantiomerically pure form. The advantage (Na SO ) and the solvent was removed on a rotary evaporator. The
2
4
of this approach is that the synthetic route is short and crude product was purified by flash chromatography (silica gel; cy-
clohexane–EtOAc, 20:1, R 0.31) affording (±)-9-decenyl 2-(ally-
loxy)propanoate (10c).
flexible enough to synthesize various analogs for the
f
Synthesis 2003, No. 3, 365–370 ISSN 0039-7881 © Thieme Stuttgart · New York

3
68
M. Eh
PAPER
Yield: 3.60 g (70%); colorless oil.
1,4-Dioxacyclopentadec-(E/Z)-6-en-2-one (11a)
R 0.31 (cyclohexane–EtOAc, 30:1); odor: musky, metallic, remi-
f
niscent of hot iron; ratio of isomers E–Z = 3.5:1.
1
H NMR (200 MHz, CDCl ): δ = 1.25–1.40 (m, 10 H), 1.42 (d,
3
J = 6.9 Hz, 3 H), 1.57–1.74 (m, 2 H), 1.97–2.13 (m, 2 H), 3.94 (ddd,
J = 12.5, 5.9, 1.7 Hz, 2 H), 4.02 (q, J = 6.7 Hz, 1 H), 4.14 (m, 2 H),
1
H NMR (200 MHz, CDCl ): δ = 1.20–1.50 (m, 10 H), 1.55–1.80
3
4
1
.93 (ddd, 1 H, J = 10.2, 2.2, 1.1 Hz, 1 H), 4.99 (ddd, J = 17.2, 2.2,
.4 Hz, 1 H), 5.20 (ddd, J = 10.2, 1.7, 1.3 Hz, 1 H), 5.29 (dq,
(m, 2 H), 2.0–2.16 (m, 2 H), 4.09 (s, 2 H), 4.11–4.33 (m, 4 H), 5.43–
5.75 (m, 2 H).
J = 17.2, 1.7 Hz, 1 H), 5.81 (ddd, J = 17.2, 10.2, 6.7 Hz, 1 H), 5.93
13
C NMR (50 MHz, CDCl ): δ = 23.1, 25.2, 26.1, 26.5, 27.3, 27.5,
3
(
dddd, J = 17.2, 10.2, 6.0, 5.2 Hz, 1 H).
3
1.2, 64.2, 65.7, 72.6, 126.6, 136.6, 171.2.
1
3
C NMR (50 MHz, CDCl ): δ = 18.7, 25.8, 28.5, 28.8, 29.0, 29.1,
+
+
+
3
MS: m/z (%) = 41 (C H , 100), 55 (C H , 75), 67 (C H ,61), 81
3
5
4
7
+
5
7
2
9.3, 33.7, 64.9, 71.0, 74.0, 114.1, 117.7, 134.1, 139.1, 173.4.
+
+
+
(
C H , 40), 95 (C H , 19), 109 (C H , 9), 123 (C H , 6), 148
6
+
9
7
11
8
13
9
15
+
+
+
+
+
MS: m/z (%) = 41 (C H , 79), 43 (C H O , 64), 55 (C H , 29), 69
(M – C H O , 2), 166 (M – C H O , 1), 184 (M – C H O, 2), 198
(M – CO, 1).
3
5
2
3
+
4
7
2 6 3 2 4 2 2 2
+
+
+
+
(
C H , 11), 83 (C H , 10), 85 (C H O , 100), 138 (C H , 4).
5
9
6
11
5
9
10 18
(
)-3-Methyl-1,4-dioxacyclopentadec-(E/Z)-6-en-2-one (11c)
1,4-Dioxacyclopentadecan-2-one (12a)
In a 500 mL, 3-necked flask fitted with condenser, dropping funnel
R 0.33 (cyclohexane–EtOAc, 30:1); odor: musky, floral, metallic,
f
and thermometer (±)-9-decenyl 2-(allyloxy)propanoate (10c) (187
erogenous.
mg, 0.70 mmol) and Ti(i-PrO) (60.0 mg, 0.21 mmol) were dis-
1
4
H NMR (200 MHz, CDCl ): δ = 1.30–1.51 (m, 14 H), 1.60–1.80
m, 4 H), 3.52 (t, J = 6.6 Hz, 2 H), 4.11 (s, 2 H), 4.22 (dd, J = 5.1,
.4 Hz, 2 H).
3
solved in CH Cl (220 mL) under N and the mixture was refluxed
2
2
2
(
4
for 1 h. A solution of the ruthenium carbene 13 (16.4 mg, 0.02
mmol) in CH Cl (5 mL) was added and refluxed for 20 h. After the
2
2
1
3
C NMR (50 MHz, CDCl ): δ = 23.7, 24.7, 25.3, 25.5, 26.2, 26.6,
mixture had cooled to r.t. the organic layer was washed with aq HCl
1 M; 50 mL), the layers were separated and the organic layer was
3
2
6.9, 27.7, 28.0, 65.3, 69.3, 71.9, 171.3.
(
filtered through a short pad of silica gel, and the solvent was re-
moved on a rotary evaporator. Flash chromatography (silica gel; cy-
+
+
+
MS: m/z (%) = 41 (C H , 100), 55 (C H , 83), 69 (C H ,47), 83
(
(M – C H O , 1), 168 (M – C H O , 1), 183 (M – C H O, 1), 228
(
3
5
+
4
7
+
5
9
+
+
C H , 27), 95 (C H , 23), 109 (C H , 9), 121 (C H , 6), 150
6
11
7
11
8
13
9
13
clohexane–EtOAc, 30:1, R 0.26) afforded 3-methyl-1,4-
+
+
+
f
2 6 3 2 4 2 2 5
dioxacyclopentadec-(E/Z)-6-en-2-one (11c).
+
M , 1).
Yield: 160 mg (95%); colorless oil; odor: musky, sweet-floral, erog-
enous; ratio of isomers E–Z = 2.8:1.
1
,4-Dioxacyclohexadec-(E/Z)-6-en-2-one (11b)
R 0.29 (cyclohexane–EtOAc, 30:1); odor: musky, woody, techni-
cal, metallic, reminiscent of hot iron; ratio of isomers E–Z = 2.8:1.
1
f
H NMR (400 MHz, CDCl ): δ = 1.23–1.46 (m, 10 H), 1.40 (d,
3
J = 6.9 Hz, 3 H), 1.57–1.74 (m, 2 H), 1.91–2.14 (m, 2 H), 3.86–4.12
1
H NMR (200 MHz, CDCl ): δ = 1.20–1.50 (m, 12 H), 1.61–1.78
(
(
1
m, 2 H), 4.01 (q, J = 6.9 Hz, 1 H), 4.20–4.44 (m, 2 H), 5.46–5.67
m, 2 H).
3
(
m, 2 H), 2.00–2.20 (m, 2 H), 4.07–4.14 (m, 2 H), 4.10 (s, 2 H),
4
.18–4.29 (m, 2 H), 5.41–5.76 (m, 2 H).
3
C NMR (100 MHz, CDCl ): δ = 18.7, 23.3, 24.8, 26.0, 26.3, 26.8,
3
1
3
C NMR (50 MHz, CDCl ): δ = 25.3, 25.9, 26.4, 26.9, 27.6, 27.7,
2
7.6, 31.0, 64.4, 71.3, 72.8, 127.1, 135.4, 173.7.
3
2
7.9, 31.6, 64.7, 64.8, 70.8, 125.8, 137.3, 170.5.
+
+
+
MS: m/z (%) = 41 (C H , 87), 54 (C H , 100), 67 (C H ,90), 81
3
5
4
6
+
5
7
+
+
+
+
+
+
MS: m/z (%) = 41 (C H , 100), 55 (C H , 70), 67 (C H , 54), 81
(C H , 39), 95 (C H , 25), 109 (C H , 8), 121 (C H , 8), 162
(
C H , 66), 95 (C H , 36), 123 (C H , 8), 149 (M – C H O , 8),
67 (M – C H O , 3), 184 (M – C H O, 6), 240 (M , 2).
3
5
4
7
+
5
7
6
9
7
11
9
15
3
7
3
+
+
+
+
+
+
1
6
+
9
7
11
8
13
9
13
3
5
2
3
4
+
+
(
M – C H O , 1), 180 (M – C H O , 1), 198 (M – C H O, 1).
2 6 3 2 4 2 2 2
(
)-3-Methyl-1,4-dioxacyclopentadecan-2-one (12c)
1
,4-Dioxacyclohexadecan-2-one (12b)
In the presence of 10% Pd/C (0.01 g, 0.01 mmol, 1.00 mol%) a so-
lution of 3-methyl-1,4-dioxacyclopentadec-(E/Z)-6-en-2-one (11c)
R 0.29 (cyclohexane–EtOAc, 30:1); odor: musky, woody, techni-
cal, metallic, erogenous.
f
(240 mg, 1.00 mmol) in i-PrOH (10 mL) was hydrogenated with H2
(1 bar) over 3 h. The catalyst was removed by vacuum filtration
1
H NMR (200 MHz, CDCl ): δ = 1.25–1.51 (m, 16 H), 1.55–1.75
3
over a pad of Celite, and the filtrate was concentrated in a rotary
evaporator. Flash chromatography (silica gel; cyclohexane–EtOAc,
3
(
5
m, 2 H), 3.53 (t, J = 5.8 Hz, 2 H), 4.08 (s, 2 H), 4.24 (dd, J = 5.2,
.1 Hz, 2 H).
0:1, R 0.28) afforded 3-methyl-1,4-dioxacyclopentadecan-2-one
f
13
C NMR (50 MHz, CDCl ): δ = 24.2, 24.3, 25.3, 25.4, 26.5, 26.6,
3
(
12c).
2
6.8, 26.9, 28.1, 28.5, 64.8, 69.0, 71.2, 170.5.
Yield: 177 mg (74%); colorless oil; odor: musky, sweet-floral, am-
bergris, erogenous, reminiscent of musk ambrette.
+
+
+
MS: m/z (%) = 41 (C H , 100), 55 (C H , 85), 69 (C H ,43), 83
3
5
+
4
7
+
5
9
+
+
(
C H , 33), 95 (C H , 22), 109 (C H , 9), 121 (C H , 6), 153
6
+
11
7
11
8
13
9
13
1
H NMR (200 MHz, CDCl ): δ = 1.20–1.50 (m, 14 H), 1.40 (d,
+
+
3
(M – C H O , 1), 171 (M – C H O , 1), 183 (M – C H O , 1), 197
3 5 3 3 3 2 2 3 2
J = 6.8 Hz, 3 H), 1.57–1.80 (m, 4 H), 3.50 (m, 2 H), 3.99 (q, J = 6.8
Hz, 1 H), 4.20 (ddd, J = 6.1, 4.7, 1.3 Hz, 2 H).
+
(
M – C H O, 1).
2 5
1
3
( )-3-Methyl-1,4-dioxacyclohexadec-(E/Z)-6-en-2-one (11d)
C NMR (50 MHz, CDCl ): δ = 18.6, 23.3, 24.5, 24.9, 25.2, 26.2,
3
R 0.25 (cyclohexane–EtOAc, 30:1); odor: musky, woody, eroge-
2
6.3, 26.5, 27.7, 28.2, 64.9, 70.4, 75.6, 174.1.
f
nous, animalic; ratio of isomers E–Z = 1.9:1.
+
+
+
MS: m/z (%) = 41 (C H , 100), 55 (C H , 96), 69 (C H , 56), 83
(
(
3
5
+
4
7
5
9
1
+
+
+
H NMR (200 MHz, CDCl ): δ = 1.22–1.53 (m, 12 H), 1.40 (d,
C H , 39), 97 (C H , 22), 110 (C H , 6), 124 (C H , 3), 169
M – C H O , 1), 183 (M – C H O , 3), 199 (M – C H O, 1).
3
6
+
11
7
13
8
14
9
16
+
+
J = 6.8 Hz, 3 H), 1.65 (m, 2 H), 2.11 (m, 2 H), 3.96–4.36 (m, 4 H),
3
5
2
2
3
2
2
3
4
.10 (q, J = 6.8 Hz, 1 H), 5.48–5.69 (m, 2 H).
Compounds 8a,c, 10a,b,d,e–12a,b,d,e were prepared according to
the same procedures as described for (±)-3-methyl-1,4-dioxacyclo-
pentadecan-2-one (12c), and purified by flash chromatography (sil-
ica gel).
1
3
C NMR (50 MHz, CDCl ): δ = 18.2, 24.9, 25.4, 26.1, 26.3, 27.1,
3
2
7.5, 28.0, 31.3, 64.6, 69.8, 71.5, 126.4, 135.7, 173.4.
+
+
+
MS: m/z (%) = 41 (C H , 100), 55 (C H , 83), 67 (C H ,68), 81
(
3
5
4
7
5
7
+
+
+
+
C H , 50), 95 (C H , 31), 109 (C H , 11), 121 (C H , 8), 163
6 9 7 11 8 13 9 13
Synthesis 2003, No. 3, 365–370 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
1,4-Dioxamacrolides: Preparation and Sensory Properties
369
+
+
+
(
(
M – C H O , 2), 181 (M – C H O , 1), 198 (M – C H O, 2), 239
the reaction mixture was allowed to cool and the Ti(i-PrO) was hy-
drolyzed by adding a small amount of water (10 drops). Flash chro-
3
7
3
3
5
2
3
4
4
+
+
M – CH , 1), 254 (M , 1).
3
matography (silica gel; cyclohexane–EtOAc, 20:1, R 0.31)
f
(
)-3-Methyl-1,4-dioxacyclohexadecan-2-one (12d)
afforded (2R)-(+)-9-decenyl-2-(allyloxy)propanoate [(R)-10c].
Yield: 4.20 g (80%); colorless oil; 99.0% ee; [α]D20 +48.2 (neat).
The spectral data were identical to those of the racemate (±)-10c.
R 0.27 (cyclohexane–EtOAc, 30:1); odor: musky, woody, amber-
gris, erogenous, animalic, reminiscent of nitro-musk.
f
1
H NMR (200 MHz, CDCl ): δ = 1.25–1.50 (m, 16 H), 1.40 (d,
3
The following RCM and the final hydrogenation were carried out
according to the procedures as described for (±)-3-methyl-1,4-diox-
acyclopentadecan-2-one (12c).
J = 6.7 Hz, 3 H), 1.53–1.76 (m, 4 H), 3.31–3.63 (m, 2 H), 3.99 (q,
J = 6.7 Hz, 1 H), 4.21 (dd, J = 5.6, 5.0 Hz, 2 H)
1
3
C NMR (50 MHz, CDCl ): δ = 18.1, 24.2, 24.6, 25.4, 26.5, 26.6,
3
2
6.7, 26.8, 26.9, 28.4, 28.7, 64.8, 69.9, 75.5, 173.6.
(
3R)-(+)-3-Methyl-1,4-dioxacyclopentadec-(E/Z)-6-en-2-one
+
+
+
MS: m/z (%) = 41 (C H , 78), 55 (C H , 100), 69 (C H ,67), 83
[(R)-11c]
3
5
4
7
5
9
+
+
+
+
(
(
(
C H , 55), 97 (C H , 30), 111 (C H , 11), 125 (C H , 3), 166
M – C H O , 3), 197 (M – C H O , 5), 241 (M – CH , 1), 256
M ).
Odor: musky, sweet-floral, ambergris, erogenous, stronger musky
and more erogenous than the racemate (±)-11c; [α]D +20.0 (neat).
6
11
7
13
8
15
9
17
+
+
+
20
3
6
3
2
3
2
3
+
The spectral data were identical to those of the racemate (±)-11c.
(
)-3-Methyl-1,4-dioxacycloheptadec-(E/Z)-7-en-2-one (11e)
(
3R)-(+)-3-Methyl-1,4-dioxacyclopentadecan-2-one [(R)-12c]
R 0.27 (cyclohexane–EtOAc, 30:1); odor: musky, sweet-woody,
erogenous; ratio of isomers E–Z = 1.8:1.
f
Odor: musky, sweet-floral, ambergris, erogenous, animalic, remi-
niscent of musk ambrette, stronger musky than the racemate (±)-
12c; 99.0% ee; [α]D +20.4 (neat).
1
20
H NMR (200 MHz, CDCl ): δ = 1.20–1.44 (m, 12 H), 1.40 (d,
3
J = 6.8 Hz, 3 H), 1.60–1.75 (m, 2 H), 1.98–2.10 (m, 2 H), 2.25–2.37
The spectral data were identical to those of the racemate (±)-12c.
(
(
1
m, 2 H), 3.34–3.60 (m, 2 H), 4.00 (q, J = 6.8 Hz, 1 H), 4.15–4.28
m, 2 H), 5.40–5.50 (m, 2 H).
Compounds (S)-11c,d, (S)-12c,d, (R)-11d and (R)-12d were pre-
pared according to the same procedures as described for (3R)-(+)-3-
methyl-1,4-dioxacyclopentadecan-2-one [(R)-12c], and purified by
flash chromatography (silica gel). In all cases the spectral data of the
enantiomers were identical to those of the corresponding racemates.
3
C NMR (50 MHz, CDCl ): δ = 18.5, 25.8, 27.1, 27.5, 27.7, 27.8,
3
2
8.6, 28.7, 31.6, 32.9, 65.0, 70.5, 75.5, 126.0, 132.9, 173.6.
+
+
+
MS: m/z (%) = 41 (C H , 43), 55 (C H , 88), 67 (C H , 100), 81
3
5
+
4
7
5
7
+
+
+
(
1
–
C H , 74), 96 (C H , 44), 110 (C H , 20), 121 (C H , 18),
6 9 7 12 8 14 9 13
+
+
+
+
35 (C H , 15), 149 (C H , 8), 178 (M – C H O , 13), 197 (M
(3S)-(–)-3-Methyl-1,4-dioxacyclopentadec-(E/Z)-6-en-2-one
[(S)-11c]
10
15
11 17
3
6
3
+
+
C H O , 1), 225 (M – C H O, 1), 268 (M , 1).
3
3
2
2
3
Odor: slightly musky, sweet-floral, weaker than the racemate (±)-
2
0
(
)-3-Methyl-1,4-dioxacycloheptadecan-2-one (12e)
11c; [α]D –20.0 (neat).
R 0.28 (cyclohexane–EtOAc, 30:1); odor: musky, sweet-woody,
ambergris, erogenous, reminiscent of musk ambrette.
f
The spectral data were identical to those of the racemate (±)-11c.
1
H NMR (200 MHz, CDCl ): δ = 1.26–1.44 (m, 18 H), 1.40 (d,
(3S)-(–)-3-Methyl-1,4-dioxacyclopentadecan-2-one [(S)-12c]
Odor: musky, sweet-floral, ambergris, erogenous, animalic, remi-
niscent of musk ambrette, weaker than the racemate (±)-12c; 95.2%
3
J = 6.8 Hz, 3 H), 1.55–1.75 (m, 4 H), 3.38–3.60 (m, 2 H), 3.79 (q,
J = 6.8 Hz, 1 H), 4.10–4.30 (m, 2 H).
2
0
1
3
ee; [α]
D
–23.0 (neat).
C NMR (50 MHz, CDCl ): δ = 18.6, 24.7, 25.3, 26.1, 26.4, 26.6,
3
2
6.7, 27.1, 27.3, 27.4, 28.6, 28.7, 64.9, 70.3, 75.5, 173.7.
The spectral data were identical to those of the racemate (±)-12c.
+
+
+
MS: m/z (%) = 41 (C H , 91), 55 (C H , 100), 69 (C H , 65), 83
3
5
+
4
7
5
9
+
+
+
(3R)-(+)-3-Methyl-1,4-dioxacyclohexadec-(E/Z)-6-en-2-one
[(R)-11d]
(
(
C H , 54), 97 (C H , 37), 111 (C H , 14), 123 (C H , 6), 137
6 11 7 13 8 15 9 15
+
+
+
+
C H , 15), 152 (C H , 2), 180 (M – C H O , 1), 197 (M –
1
0
17
11 20
3
6
3
+
+
+
Odor: musky, woody, ambergris, erogenous, animalic, stronger
C H O , 1), 211 (M – C H O , 5), 241 (M – CHO, 1), 270 (M , 1).
3
5
2
2
3
2
20
musky than the racemate (±)-11d; [α]D +28.2 (neat).
(
(
3R)-(+)-3-Methyl-1,4-dioxacyclopentadecan-2-one [(R)-12c]
2R)-(+)-Isobutyl-2-(allyloxy)propanoate (18)
The spectral data were identical to those of the racemate (±)-11d.
Under N atmosphere (2R)-(+)-isobutyl-2-hydroxypropanoate (15)
(3R)-(+)-3-Methyl-1,4-dioxacyclohexadecan-2-one [(R)-12d]
Odor: strong musky, woody, ambergris, erogenous, animalic, remi-
niscent of musk ambrette, stronger musky than the racemate (±)-
2
(
8.80 g, 60.0 mmol) was dissolved in cyclohexane (120 mL) and al-
lyl 2,2,2-trichloroethanimidoate (16) (25.0 g, 120 mmol), dissolved
in cyclohexane (30 mL), was added. Additionally, trifluo-
romethanesulfonic acid (900 mg, 6.00 mmol, 0.55 mL) was added
at r.t. Stirring of the reaction mixture over 16 h at r.t. was followed
2
0
12d; 99.0% ee; [α]D +15.4 (neat).
The spectral data were identical to those of the racemate (±)-12d.
by filtration and extraction of the filtrate with sat. aq NaHCO (75
mL). The layers were separated and the organic layer was dried
3
(
1
3S)-(–)-3-Methyl-1,4-dioxacyclohexadec-(E/Z)-6-en-2-one [(S)-
1d]
(
Na SO ), and the solvent was removed on a rotary evaporator.
2 4
Odor: slightly musky, woody, erogenous, weaker musky than the
racemate (±)-11d and no ambergris undertone; [α]D –23.0 (neat).
Flash chromatography (silica gel; cyclohexane–EtOAc, 15:1,
20
R 0.26) afforded (2R)-(+)-isobutyl-2-(allyloxy)propanoate (18).
f
The spectral data were identical to those of the racemate (±)-11d.
Yield: 8.40 g (75%); colorless oil; 99.0% ee; [α]D20 +56.1 (neat).
(
3S)-(–)-3-Methyl-1,4-dioxacyclohexadecan-2-one [(S)-12d]
(
(
9
2R)-(+)-9-Decenyl-2-(allyloxy)propanoate [(R)-10c]
2R)-(+)-Isobutyl-2-(allyloxy)propanoate (18) (3.50 g, 19.0 mmol),
Odor: musky, woody, erogenous, weaker musky than the racemate
(
20
±)-12d and no ambergris undertone; 95.2% ee; [α]D –16.0 (neat).
-decen-1-ol (9a) (4.50 g, 28.5 mmol) and Ti(i-PrO) (0.56 g, 2.00
4
The spectral data were identical to those of the racemate (±)-12d.
mmol) were heated to 80 °C under vacuum (400 mbar). After 5 h
Synthesis 2003, No. 3, 365–370 ISSN 0039-7881 © Thieme Stuttgart · New York

3
70
M. Eh
PAPER
Acknowledgment
(3) Bauer, K.; Garbe, D.; Surburg, H. Common Fragrance and
Flavor Materials; Wiley-VCH: Weinheim, 1997.
Thanks are due to H. Surburg for olfactory descriptions as well as
fruitful discussions, to P. Wörner for olfactory evaluation of the
compounds, to H. Sommer and C. O. Schmidt for spectroscopic da-
ta, to P. Werkhoff for chiral GC analysis and last but not least to B.
Brünig for experimental work.
(
4) (a) Stoll, M.; Rouvé, A. Helv. Chim. Acta 1935, 18, 1087.
b) Theimer, E. T. Fragrance Chemistry – The Science of the
(
Sense of Smell; Academic Press: New York, 1982.
5) Berends, W. Am. Perfum. Cosmet. 1965, 80, 35.
6) Kraft, P.; Cadalbert, R. Synthesis 1998, 1662.
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Soc. 1993, 115, 9858. (b) Nguyen, S. T.; Johnson, L. K.;
Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1992, 114,
(
(
(
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(
0
(
(
(
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4
Synthesis 2003, No. 3, 365–370 ISSN 0039-7881 © Thieme Stuttgart · New York